Search Results (158)

Autism spectrum disorder (ASD) involves complex genetic–environmental interactions. Prenatal valproic acid (VPA) exposure, a known environmental risk factor, induces ASD-like phenotypes in rodents, although the mechanisms linking gut microbiota dysbiosis to neurobehavioral deficits remain unclear. Evidence suggests gut–brain axis dysregulation via altered microbial diversity and reduced short-chain fatty acid (SCFA)-producing taxa contributes to ASD pathogenesis. This study investigated whether prenatal VPA exposure drives ASD-like behaviors through gut dysbiosis and SCFA-producer depletion (e.g., Clostridia, Lachnospiraceae), exploring neuroinflammation and oxidative stress as mechanisms. An ASD rat model was established by maternal VPA injection during specific gestational days. Behavioral tests assessed anxiety, sociability, repetitive behaviors, and cognition. Gut microbiota composition (16S rRNA sequencing), cytokine levels (ELISA), oxidative stress markers (biochemical assays), and microglial activation (Iba1 immunofluorescence) were analyzed. VPA-exposed offspring showed ASD-like behaviors accompanied by neurodevelopmental toxicity, manifesting as social deficits, repetitive grooming, and impaired memory. Concurrently, gut analysis revealed reduced alpha diversity and depleted SCFA-producers (e.g., Clostridia, Lachnospiraceae), alongside increased Bacteroidia and Enterobacteriaceae. Neuroinflammation (elevated IL-1β, IL-6, TNF-α, microglial activation) and oxidative stress (reduced GSH, SOD; elevated MDA, NO) were evident. Multivariate analyses linked dysbiosis to behavioral impairments. Prenatal VPA exposure induces gut microbiota dysbiosis, potentially exacerbating neuroinflammation and oxidative stress to drive ASD-like phenotypes. This establishes a mechanistic link between prenatal insults, gut–brain axis disruption, and neurodevelopmental abnormalities, highlighting microbial modulation and SCFA supplementation as potential ASD therapeutics. Furthermore, integrating behavioral, microbial, and molecular analyses advances understanding of gut–brain interactions in ASD and identifies microbiota–metabolite pathways as targets for neurodevelopmental disorders. Full article

Prenatal alcohol exposure (PAE) causes neurobehavioral deficits and metabolic syndrome in later life. Prenatal choline supplementation (PCS) improves those behavioral deficits. Here we test whether PCS also ameliorates the attendant metabolic syndrome, using an established mouse model that mirrors aspects of alcohol-related neurodevelopmental disorders. Pregnant dams were exposed to alcohol (3 g/kg) from gestational days 8.5–17.5; some dams received additional choline (175% of requirement) by a daily injection. Offspring were followed through to the age of 86 wks with respect to their body composition and glucose tolerance. We found that PAE affected these outcomes in a sex-dependent manner. Male PAE offspring exhibited an increased fat mass, liver enlargement, elevated fasting glucose, and glucose intolerance. Female PAE offspring exhibited an increased fat mass, but the glucose tolerance and fasting values were unaffected. Regardless of sex, PCS attenuated all these metabolic measures. PCS was shown previously to elevate methyl-related choline metabolites and improve fetal growth, suggesting that it acts by attenuating the in utero stressors that otherwise program the fetus for metabolic syndrome in later life. Importantly, PCS also improved the adiposity, fasting glucose, and glucose tolerance in control offspring consuming the fixed-nutrient AIN-93G diet, suggesting that its choline content (1 g/kg) may be inadequate for optimal rodent health. Full article

Background: Absence epilepsy is a common pediatric neurological disorder characterized by brief seizures and lapses in awareness. The relationship between anxiety and absence epilepsy is multifaceted. This study aims to investigate neurobehavioral signs directly and indirectly related to anxiety and potential sex differences in aged WAG/Rij rats, a well-established animal model of absence epilepsy. Methods: A battery of behavioral tests was conducted to assess various aspects of neurobehavior, including anxiety (elevated plus maze), anhedonia (sucrose preference), social function, and associative learning (fear conditioning). Multidimensional metrics assessed cognition, motor function, and exploration strategies, prioritizing anxiety as a key influencing factor. Results: Electroencephalogram (EEG) phenotyping was used to identify epileptic and non-epileptic rats. Traditional anxiety measures in the elevated plus maze did not reveal significant differences between groups. However, the Anxiety Composite Index revealed higher autonomic reactivity in non-epileptic females. Cognitive assessments showed no epilepsy- or sex-related differences in overall learning performance. Females exhibited superior avoidance learning compared males. Among epileptic males, those with poor learning performance also displayed higher anxiety-avoidance scores. Rats with high anxiety levels showed enhanced socio-affective reactivity and passive coping, with no effect on exploratory learning. Conclusions: Our findings highlight the importance of sex-specific analyses and physiological measures in epilepsy research. Neurobehavioral comorbidities in WAG/Rij rat model are significantly influenced by anxiety-like behavioral phenotype. Enhanced phenotyping of rat models of absence epilepsy can improve its translational value in understanding epilepsy-associated psychiatric disorders. Full article

Chronic hydrocephalus following aneurysmal subarachnoid hemorrhage (SAH) is a complication that can lead to deterioration in neurological status and cognitive impairment. Our recent clinical study reported that a high concentration of plasma fibulin-5 (FBLN5), a matricellular protein, was associated with the occurrence of chronic hydrocephalus after SAH. This study aimed to investigate whether and how FBLN5 was associated with hydrocephalus during acute to later phases of SAH in mice. C57BL/6 male mice underwent sham or filament perforation SAH modeling, and vehicle or two dosages (0.01 and 0.1 μg) of short or long recombinant FBLN5 (rFBLN5) were randomly administrated by an intracerebroventricular injection. Neurobehavioral tests, measurements of the degree of ventricular enlargement, Western blotting, and immunohistochemical staining were performed to evaluate hydrocephalus 24 and 48 h after SAH. After SAH, ventricular dilatation did not occur at 24 h but developed at 48 h, and both doses of long rFBLN5 with an arginine–glycine–aspartic acid domain suppressed ventricular dilatation at 48 h after SAH. Long rFBLN5 also decreased phosphorylated p38 in the brain parenchyma and prevented post-SAH increases in perivascular macrophages, as well as microglia activation in the brain parenchyma at 48 h after SAH. Although further research is required to clarify the detailed mechanism, this study demonstrated for the first time that exogenous administration of FBLN5 may have a protective effect against ventricular dilatation after experimental SAH. Full article

Background: Measurements are necessary in rehabilitation for evaluating service effectiveness. The ADL-focused Occupation-based Neurobehavioral Evaluation (A-ONE) is used for evaluating ADL performance and the impact of neurobehavioral impairments on the performance. Recently, Rasch-based software was constructed for the A-ONE ADL and neurobehavioral scales. It converts ordinal rating scale scores into measures, estimates missing data values and calculates the statistical significance of changes. Objectives: To expand the A-ONE software by developing a cerebrovascular accident (CVA) neurobehavioral subscale. Additionally, to pilot-test whether the ADL and CVA scales of the software can detect statistically significant improvements. Method: Rasch analysis was used for evaluating the item fit, PCA, person separation and reliability to establish the internal validity of the CVA subscale (n = 222). The external validity (n = 22) was obtained by comparing A-ONE software measures to Winsteps measures. Subsequently 21 pre–post-intervention comparisons were made of stroke patients using both the ADL and CVA scales. Results: All set criteria for internal and external validity were met. By using the software clinically after incorporating the CVA subscale, statistically significant changes were detected in 90.5% of comparisons using the ADL scale and 36.4% using the CVA scale. The intervention program used was determined to consist of 66.4% occupation-based activities. Conclusions: This study is the first to deliver a clinically deployable Rasch-based CVA subscale integrated into routine occupational therapy software. The A-ONE software offers considerable time saving for therapists and the potential to detect significant differences in performance and impairment impact. It contributes to the removal of clinical obstacles toward the use of the instrument as an outcome measure and encourages the use of measures in rehabilitation. Full article

Obstructive sleep apnea (OSA) is a prevalent disorder linked to metabolic complications such as diabetes and cardiovascular disease. By fragmenting normal sleep architecture, OSA perturbs the growth hormone/insulin-like growth factor (GH/IGF) axis and alters circulating levels of IGF-binding proteins (IGFBPs). A prior clinical observation of elevated IGFBP4 in OSA patients motivated the present investigation in a controlled animal model. Building on the previously reported protocol, OSA was induced in male C57BL/6 mice (9–12 weeks old) through intralingual injection of polytetrafluoroethylene (PTFE), producing tongue hypertrophy, intermittent airway obstruction, and hypoxemia. After 8–10 weeks, the study assessed (1) hypoxia biomarkers—including HIF-1α and VEGF expression—and (2) neurobehavioral outcomes in anxiety and cognition using the open-field and novel object recognition tests. PTFE-treated mice exhibited a significant increase in circulating IGFBP4 versus both baseline and control groups. Hepatic Igfbp4 mRNA was also upregulated. Behaviorally, PTFE mice displayed heightened anxiety-like behavior and impaired novel object recognition, paralleling cognitive deficits reported in human OSA. These findings validate the PTFE-induced model as a tool for studying OSA-related hypoxia and neurocognitive dysfunction, and they underscore IGFBP4 as a promising biomarker and potential mediator of OSA’s systemic effects. Full article

Stress is a major factor that threatens the body’s homeostasis or well-being. Excessive stress causes psychological anxiety and tension, which disrupts the balance of the autonomic nervous system that maintains the body’s balance, resulting in hormonal imbalance and brain changes. In this study, we investigated the effects of Withania somnifera (Ashwagandha) extract on depression, neurobehavior, and hippocampal changes in model mice exposed to stress. Using an excessive restraint stress-induced depression model, we measured the behavioral changes and the levels of brain-derived neurotrophic factor (BDNF) and antioxidant genes in five groups: control, stress, low-dose W. somniferous extract (20 mg/kg/day), high-dose W. somniferous extract (40 mg/kg/day), and L-theanine (50 mg/kg/day, positive control). Stressed mice showed poorer performance in the open field and elevated plus maze tests compared with the control group. The impaired performance was restored following W. somniferous extract administration. In addition, W. somniferous extract restored the decreased expression of BDNF in the hippocampus caused by restraint stress, improved the balance of stress hormones (i.e., cortisol, dopamine, and norepinephrine), and also regulated BDNF, inflammatory genes, and antioxidant genes in brain tissue. Therefore, W. somniferous extract can induce antidepressant and anti-stress effects by maintaining brain BDNF expression and preventing hippocampal tissue alterations caused by restraint stress. Full article

Background/Objectives: Silicon dioxide nanoparticles (SiO₂NPs) do not exist in isolation in the environment but can interact with other substances, thus influencing their toxic effects on aquatic organisms. We assessed the combined impact of SiO₂NPs and N-acetylcysteine (NAC), an antioxidant with the potential to counteract nanoparticle-induced oxidative stress (OS). Methods: Behavioral assessments, including the social interaction test and color preference test, were performed to evaluate neurobehavioral changes. OS biomarkers, including malondialdehyde (MDA) levels for lipid peroxidation and the activity of key antioxidant enzymes such as glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD), were assessed to evaluate the extent of cellular damage. Results: The results indicate that prolonged exposure to SiO₂NPs induces significant behavioral disruptions, including reduced exploratory behavior and increased anxiety-like responses. Furthermore, biochemical analysis revealed increased OS, suggesting nanoparticle-induced cellular toxicity. NAC co-treatment partially reversed these effects, particularly improving locomotor outcomes and antioxidant response, but was less effective on social behavior. Conclusions: These findings highlight the ecological and health risks posed by SiO₂NPs and point toward the need for further toxicological studies on their long-term biological effects. Full article

Astrocyte activation and gender differences play critical roles in the prognosis following stroke. Recent studies have shown that optogenetic technology can promote brain repair after stroke by activating astrocytes in male rats. However, it remains unclear whether gender differences influence the efficacy of optogenetic activation of astrocytes in regulating post-stroke brain repair and its underlying mechanisms. In this study, we activated astrocytes in the ipsilateral cortex of adult glial fibrillary acidic protein-channelrhodopsin 2-enhanced yellow fluorescent protein (GFAP-ChR2-EYFP) transgenic Sprague Dawley rats using optogenetic stimulation at 24, 36, 48, and 60 h after inducing photothrombosis stroke. Neurobehavioral tests, cresyl violet staining, RT-qPCR, Western blot, and immunofluorescence analysis were performed on both female and male rats. Our results showed that male rats exhibited significant improvements in behavioral scores and reduction in infarct size after optogenetic activation of astrocytes at three days post-stroke (p < 0.05), whereas no significant changes were observed in female rats. Additionally, in female rats, the expression of basic fibroblast growth factor (bFGF) increased after ischemic stroke and astrocytic optogenetic stimulation (p < 0.05), leading to enhanced endothelial cell proliferation compared to male rats (p < 0.05). In vitro experiments further demonstrated that the astrocyte activation was inhibited in the presence of bFGF (p < 0.05). These findings suggest that the increase in bFGF levels in females following stroke may inhibit the optogenetic activation of astrocytes, thereby attenuating the therapeutic effect of astrocyte activation on post-stroke brain repair. This study provides important insights into the gender-specific roles of astrocytes in the acute phase of ischemic stroke. Full article

Kernicterus spectrum disorder is the permanent and highly disabling neurologic sequel of neonatal exposure to hyperbilirubinemia, presenting, among other symptoms, variable and untreatable motor disabilities. To search for potential biomolecular explanations, we used a Gunn rat colony exhibiting spontaneous hyperbilirubinemia and a large variability of motor deficits on a beam-walking test. Histological and microscopic analyses confirmed worsening damage in the cerebellum (Cll; hypoplasia, increased death of neurons, and disrupted astroglial structures) and parietal motor cortex (hCtx; increased cell sufferance and astrogliosis). Clustering and network analyses of transcriptomic data reveal rearrangement of the physiological expression patterns and signaling pathways associated with bilirubin neurotoxicity. Bilirubin content among hyperbilirubinemic (jj) animals is overlapped, which suggests that the amount of bilirubin challenge does not fully explain the tissue, transcriptomic, proteomic, and neurobehavioral alterations. The expression of nine genes involved in key postnatal brain development processes is permanently altered in a phenotype-dependent manner. Among them, Grm1, a metabotropic glutamatergic receptor involved in glutamate neurotoxicity, is consistently downregulated in both brain regions both at the transcriptomic and proteomic levels. Our results support the role of Grm1 and glutamate as biomolecular markers of ongoing bilirubin neurotoxicity, suggesting the possibility to improve diagnosis by ¹H-MR spectroscopy. Full article

Background/Objective: The Trail Making Test (TMT) is a widely used neuropsychological tool to assess processing speed (Part A) and executive function (Part B). However, the neuroanatomical substrates underlying its Black & White variant (TMT-B&W) and the influence of demographic factors remain poorly understood. This study aimed to identify gray matter (GM) correlates of TMT-B&W performance across unadjusted and covariate-adjusted models in cognitively healthy adults. Methods: In this cross-sectional study, 87 participants (40–80 years) underwent structural magnetic resonance imaging (MRI) and completed TMT-B&W. Whole-brain voxel-based morphometry (VBM) was conducted using FreeSurfer for preprocessing and Computational Anatomy Toolbox (CAT12)/Statistical Parametric Mapping (SPM12) for analysis. Two voxel-wise regression models (unadjusted and adjusted for age, education, gender, and total intracranial volume (TICV)) assessed GM associations with TMT-B&W-A-B performance. Statistical thresholds were voxel-level p < 0.001 (uncorrected) and cluster-level Family-Wise Error (FWE) correction (p < 0.001). Results: In unadjusted models, TMT-B&W-A performance correlated with GM reductions in the right orbitofrontal cortex (T = 42.64, equivk = 515.60, representing peak voxel level T-statistic and cluster size in voxels), while TMT-B&W-B linked to the right insular cortex (T = 50.65, equivk = 515.50). After adjustment, both tasks converged on the left thalamus (TMT-A: T = 8.05, equivk = 594; TMT-B: T = 8.11, equivk = 621), with TMT-B&W-B showing a denser thalamic cluster. Demographic covariates attenuated cortical associations, revealing thalamic integration as a shared mechanism. Conclusions: The thalamus emerges as a critical hub for TMT-B&W performance when accounting for demographic variation, while distinct cortical regions mediate task-specific demands in unadjusted models. These findings support the TMT-B&W as a practical, low-cost neurobehavioral marker of brain integrity in older populations. Full article

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder, with lead (Pb) exposure increasingly linked to its risk. However, the molecular mechanisms linking Pb to ASD remain poorly understood. This study established a postnatal Pb-exposed mouse model and employed the three-chamber social test and the marble-burying test to assess ASD-like behavioral phenotypes. The Pb levels in both blood and the hippocampus were quantified, and hippocampal neurons were assessed for morphological alterations. Moreover, a Tandem Mass Tag (TMT)-based quantitative proteomics approach was applied to elucidate the underlying mechanisms. Neurobehavioral experiments revealed Pb-exposed C57BL/6 offspring exhibited reduced social interaction and novelty preference along with increased repetitive marble-burying behavior. The Pb levels in both the blood and hippocampus of Pb-treated mice were significantly elevated compared with those of control animals. Postnatal Pb exposure resulted in a reduction in the neuronal numbers and disorganized neuronal arrangement in the hippocampus. A total of 66 proteins were identified as being differentially expressed after postnatal Pb exposure. Among them, 34 differentially expressed proteins were common in both Pb exposure groups, with 33 downregulated and 1 upregulated. Bioinformatic analysis revealed multi-pathway regulation involved in Pb-induced neurodevelopmental disorders, including dysregulation of synaptic signaling, abnormal activation of neuron apoptosis, and neuroinflammation. Notably, the SYT10/IGF-1 signaling pathway may play a potential key role. These findings enhance understanding of Pb-induced autism-like behaviors, providing novel proteomic insights into the etiology of ASD. Full article

Background: Chronic ischemic stroke presents a significant challenge in neurology, with limited therapeutic options available for long-term recovery. During cerebral infarction, anti-inflammatory phenotype microglia/macrophages produce anti-inflammatory cytokines and neurotrophic factors that facilitate the process of brain repair. However, obtaining sufficient anti-inflammatory microglia/macrophages from the human central nervous system is challenging. Bone marrow-derived inducible microglia-like cells (BM-iMGs) with an anti-inflammatory microglial phenotype were explored to induce neuroprotective properties. Here, we transplanted BM-iMGs into the brain of middle cerebral artery occlusion (MCAO) model male mice to explore their potential for treating chronic ischemic stroke. Methods: Bone marrow-derived mononuclear cells (BM-MNCs) were isolated from green fluorescent protein mice and incubated with granulocyte–macrophage colony-stimulating factor (GM-CSF) and IL-4 to induce BM-iMGs with an anti-inflammatory phenotype. BM-iMGs were transplanted into the brains of mice on day 14 after MCAO, and behavioral tests, histology, cerebral blood flow, and gene expression were evaluated. Results: An intracranial injection of BM-iMGs promoted neurobehavioral recovery, reduced neuronal cell loss, suppressed neuroinflammatory astrocytic and microglial responses in the brain, and increased cortical surface cerebral blood flow in MCAO mice. Furthermore, neuroprotective genes were upregulated, whereas proinflammatory genes were downregulated. Conclusions: The intracranial injection of BM-iMG cells shows significant potential as a novel therapy for chronic ischemic stroke. Full article

Polychlorinated biphenyls (PCBs) are synthetic chemical compounds that have bioaccumulated and contaminated the entire global ecosystem, causing neurotoxic effects. However, polyphenols may have protective effects against this neurotoxicity. We aimed to investigate the neuroprotective effect of a hydroalcoholic extract of fresh leaves of Alpinia zerumbet (ALE), which is rich in polyphenols, on the neurobehavioral changes induced by 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). We divided C57BL/6 male mice into four groups (n = 40): Control, Control + ALE, PCB, and PCB + ALE. We administered the ALE (50 mg/kg/day) through drinking water and PCB 126 (2 mg/kg/once a week) intraperitoneally for four weeks. The mice were subjected to the elevated plus maze (EPM) and open field (OF) tests in the last week of treatment. PCB 126 reduced locomotor activity, DOPAC levels, dopamine turnover, and D2 receptor expression. This compound also increased lipid peroxidation, tyrosine levels, and BAX expression in the cerebral cortex. Notably, ALE treatment prevented locomotor activity reduction and increased DOPAC levels, dopamine turnover, and D2 receptor expression. Moreover, the extract prevented the PCB-induced increases in BAX expression and lipid peroxidation. Finally, the ALE increased SOD antioxidant activity. Our investigation highlights that using the ALE may serve as a therapeutic strategy against PCB-induced neurotoxicity. Full article

In this study, we assessed the ability of 2-Cl-MGV-1 (2-chlorophenyl quinazolin-4-yl, dimethyl carbamate), a ligand of the 18 kDa mitochondrial translocator protein (TSPO), to mitigate brain damage in a mouse model of traumatic brain injury (TBI). TSPO is important for arresting the death of neurons and glia and counteracting microglial activation, and it provides anti-inflammatory activity, promotes regeneration (including neurons), and contributes to angiogenesis. We assessed the minimal dose of the TSPO ligand 2-Cl-MGV-1 that attenuates the magnitude of brain damage as well as the time window following TBI in which the treatment is effective. We found that 7.5 mg/kg of 2-Cl-MGV-1 can reduce the impact of the TBI as assessed by magnetic resonance imaging (MRI). We also found that 2-Cl-MGV-1 improved motor performance as observed in a treadmill test (80.9% fewer shocks needed and 40.7% more distance covered, both p < 0.05), and reduced anatomical brain damage (by 86.5%, p < 0.05), cell death (by 75.0%, p < 0.001), and microglial inflammatory response (by 50.2%, p < 0.01). The treatment also increased expression of neuronal markers NeuN and β3-tubulin (30.0%, p < 0.01; 36.0%, p < 0.01, respectively). The time window in which we found the treatment to be effective was 3–11 h after TBI. Our study suggests that agents active at the TSPO can significantly attenuate the outcome of TBI, including in the structural, cellular, and neuro-behavioral dimensions. The mechanisms involved in the attenuation of brain damage following TBI may be related to a decrease in cell death and to anti-inflammatory activity. TSPO seems to be a novel target for the development of agents aimed at the suppression of neurodegenerative processes. Full article